Diffusion governs elements of such biological processes as enzymatic activity, signal transduction, gene expression, cytoskeletal remodeling,and intercellular communication. The broad objectives of this work are to provide new computer simulation tools that will enable the detailed analysis of the role of molecular diffusion in biological processes at the subcellular and cellular levels, and the application of these tools to selected problems where close contact with experimental work is possible. Specific aims for the next project period include the following. (a) Methods will be developed to allow more detailed interaction models to be used in Brownian dynamics simulations of biomolecular diffusion. (b) Methods will be developed to allow more rapid calculation of electrostatic interactions of large molecules (>100,000 atoms) during Brownian dynamics simulations. (c) Methods will be developed to allow simulations of diffusional processes at cellular scales. (d) Applications will be made to protein-protein diffusional encounter, to protein-membrane diffusional encounter, and to diffusion and reaction of neurotransmitter in model synapses. Training of undergraduate, graduate and postdoctoral students will continue to be a key aspect of this project.